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Pharmacokinetics of lidocaine after bilateral ESP block
  1. Alessandro De Cassai1,
  2. Claudio Bonanno2,
  3. Roberto Padrini2,
  4. Federico Geraldini1,
  5. Annalisa Boscolo1,
  6. Paolo Navalesi1,2 and
  7. Marina Munari1
  1. 1 UOC Anesthesia and Intensiva Care Unit, Padua University Hospital, Padova, Italy
  2. 2 Department of Medicine, DIMED, Università degli Studi di Padova, Padova, Italy
  1. Correspondence to Dr Alessandro De Cassai, UOC Anesthesia and Intensiva Care Unit, Padua University Hospital, Padova 35127, Veneto, Italy; alessandro.decassai{at}gmail.com

Abstract

Introduction Erector spinae plane (ESP) block is an emerging interfascial block with a wide range of indications for perioperative analgesia and chronic pain treatment. Recent studies have focused their attention on mechanisms of action of ESP block. However, the pharmacokinetics of drugs injected in ESP is, as of now, uninvestigated. The aim of this brief report is to investigate the pharmacokinetics of lidocaine in a series of 10 patients.

Methods We are reporting a case series of 10 patients undergoing bilateral ESP block for multilevel lumbar spine surgery.

ESP was performed with 3.5 mg/kg of lidocaine based on ideal body weight. Lidocaine concentration was dosed at 5, 15, 30 min and at 1, 2 and 3 hours.

Results Tmax was 5 min for all the patients. Cmax ranged from 1.2 to 3.8 mg/L (mean: 2.59 mg/L). AUC0-3 was high (76%, on average) suggesting an almost complete bioavailability. Age had a negative correlation with T½ of lidocaine.

Conclusions Lidocaine pharmacokinetic after ESP block is well-described by a two-compartment model with a rapid and extensive rate of absorption. Nevertheless, its peak concentrations never exceeded the accepted toxicity limit. Elimination half-life was slightly prolonged, probably due to the advanced age of some patients.

  • analgesia
  • anesthesia
  • local
  • pharmacology
  • pain management

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Introduction

Erector spinae plane (ESP) block is an emerging interfascial block with a wide range of indications for perioperative analgesia and chronic pain treatment.1 Local anesthetic (LA) is injected between the erector spinae muscle group and the underlying transverse process. Large volumes of LA are usually used (20–30 mL per block) since the extension of the block is related to the administered volume.2

Nonetheless, mechanisms of action of ESP block are still not completely understood, even if cadaveric studies showed that multiple targets are involved such as posterior and anterior spinal rami, paravertebral and epidural space.2

The pharmacokinetics of drugs injected in ESP is, to our knowledge, uninvestigated, raising LA toxicity concerns especially when bilateral blocks or high LA dose are used.

The aim of this brief report is to investigate the pharmacokinetics of lidocaine in a series of 10 patients undergoing lumbar spine surgery after bilateral ESP block.

Methods

We are presenting a case series of 10 patients undergoing lumbar spine surgery on multiple vertebral levels.

In our institution, a bilateral catheter is placed in the ESP plane as a routine procedure to improve postoperative analgesia in patients undergoing spine surgery on multiple vertebral levels. The ESP block is performed in prone position after general anesthesia induction and immediately before surgery.

The block is performed one or two levels above the intended surgery site; this is an arbitrary institutional choice in order to provide adequate analgesia while avoiding any direct contact with the surgical site while placing the catheter.

In each ESP block, a 19-gage needle is inserted in-plane to a convex-array ultrasound transducer placed in a longitudinal orientation over the tip of the transverse processes. The needle is directed in a cranial to-caudal direction. Needle correct position is confirmed by hydrolocation with 1–2 mL of normal saline, following catheter positioning. Correct catheter position is checked by ultrasound. Our dosing protocol consists of a bolus of lidocaine 3.5 mg/kg of ideal body weight (IBW) calculated by Broca’s formula (height in cm: 100)3 in 40 mL, 20 mL per side, followed, 3 hours later, by continuous infusion of 0.3% ropivacaine per side at the rate of 5 mL/hour. No LA infiltration of the wound is performed after surgery. General anesthesia is conducted according to the standard local protocol, an arterial line is inserted on all patients as our standard of care in all patients undergoing vertebral surgery on multiple levels.

To investigate the time course of lidocaine serum concentrations after an ESP block, 10 consecutive patients, aged >18 years, undergoing spine surgery were enrolled. Exclusion criteria were absolute contraindication to locoregional anesthesia, documented allergy to lidocaine, and severe liver or renal impairment.

The following demographic data were recorded: age (years), gender, height (cm), weight (kg), body surface area (m2) and body mass index (kg/m2).

After bilateral catheter positioning, lidocaine was injected as a bolus by a single operator and the time to complete the task was recorded. LA injection was performed as fast as possible respecting good clinical practice safety standards, notably a brief aspiration was performed every 5 mL and vital signs continuously monitored.

Arterial samples were obtained at 5, 15, 30 min and at 1, 2 and 3 hours after the bolus administration in order to assay lidocaine serum concentrations.

Lidocaine serum concentration in our hospital is determined at total plasma concentration by liquid chromatography–mass spectrometry (with a minimum threshold for lidocaine detection of 0.1 mg/L).

Pharmacokinetic analyses

Individual plasma concentration time profiles were first studied by non-compartmental analysis. Peak plasma lidocaine concentration (Cmax) and time to reach Cmax (Tpeak) were obtained by visual inspection and the area under the plasma concentration–time curve from 0 to 3 hours (AUC0-3) was calculated by the trapezoidal rule.

The concentration–time curves were also analyzed using both mono-compartmental and bi-compartmental models, then selecting the model yielding the best R2 value (GraphPad Prism V.8.4.1, statistical software). The slopes of the fast (α) and slow (β) decay phases were obtained and the corresponding half-lives calculated (T½ α=0.693/α and T½ β=0.693/β).

Statistical analysis

Data for each continuous variable were analyzed for a normal distribution using the Shapiro-Wilk test. Results for continuous variables with normal distributions were expressed as mean and SD values; those with non-normal distributions were expressed as median and IQR. To determine the strength and direction of association between two variables, we used the Bravais-Pearson’s correlation test. Analyzes were performed using R V.3.4.0 (2017-04-21). P values <0.05 were considered to indicate a statistically significant result.

Results

The demographic characteristics of each patient are listed in table 1.

Table 1

Patients’ demographic characteristics

No adverse reactions were reported by the patients or observed by the anesthesiologists. General anesthesia was maintained using local protocols, notably analgesia was guaranteed by remifentanil infusion (0.05 μg/kg/min–0.15 μg/kg/min) as needed.

Injections were performed in 50 s on average (range: 40–60 s). The mean time course of lidocaine serum concentrations is depicted in figure 1. In 8 of 10 patients, the two-compartment model fitted better data than one-compartment. In the other two patients, the mono-compartmental model performed better. In all cases, the mean R2 value was optimal (0.983±0.023).

Figure 1

Comparison between concentration of total arterial plasma concentration of lidocaine in our series (black circles) after 3.5 mg/kg based on ideal body weight and lidocaine blood concentration after intravenous administration of 1 mg/kg (Orlando et al 4).

The pharmacokinetic parameters calculated for each patient and the corresponding means, SDs and ranges are shown in table 2.

Table 2

Patients’ pharmacokinetic parameters

Cmax ranged between 1.2 and 3.8 mg/L (mean: 2.59 mg/L) and occurred within 5 min in all cases, suggesting a fast absorption from the injection site. However, systemic exposure during the 3-hour post-dosing period was quite variable among patients, as inferred from the wide range of AUC0-3 values (1.83–5.61 mg hour/L). In order to estimate the percentage of lidocaine absorbed into the circulation, we compared our data with those reported by Orlando et al 4 after intravenous bolus administration of 1 mg/kg lidocaine in healthy volunteers (figure 1, open circles). The ratio between the AUC0-3 of the two studies, normalized by the different doses used, suggests that intrafascial lidocaine bioavailability is 76%, on average.

Other explorative analyzes on age, weight and gender were carried out to ascertain whether any demographic characteristic could correlate with pharmacokinetic parameters. Among them, we report a significant negative correlation between age and the fast α slope (r=−0.70; p=0.036) and the slow β slope (r=−0.75; p=0.019). The results are shown in figure 2.

Figure 2

(A) Correlation between age and the fast α slope, (B) correlation between age and the slow β slope (r=−0.75; p=0.019).

Discussion

This is the first study to explore pharmacokinetics of LA administered during a bilateral ESP block. Our study shows a rapid resorption of lidocaine from the ESP. Tpeak found in our study is much shorter than that found in other studies investigating lidocaine kinetics, for example after a rectus sheath block,5 intercostal block and epidural anesthesia.6

We suppose that the injection of a large volume of LA in a wide compartment such as the ESP contributes to the high rate of absorption of the drug. A possible explanation may be a more homogeneous distribution of LA on the plane of interest during an ESP block in comparison with other blocks. Nonetheless, lidocaine Cmax never reached 5 µg/mL, which is considered the threshold for toxicity,7 suggesting that the dose of 3.5 mg/IBW-kg is safe when used to perform bilateral ESP block. The rapid absorption rate poses the risk of life-threatening adverse reactions such as LA systemic toxicity, despite the dose being calculated on IBW. For this reason future studies investigating the addition of epinephrine in order to reduce Cmax and Tmax is deemed necessary.

Similarly to what reported by other authors,8 we could not establish a significant correlation between lidocaine dose and AUC0-3.

The mean final half-life we found (3.5 hours) was somewhat longer than that reported by others after intravenous lidocaine administration (1.5–2 hours).9 This may be partly due to the inclusion in our population of patients aged over 65. Actually, an influence of age on lidocaine T½ has been reported10 and our data confirmed that patients’ age is inversely correlated with the slope (β) of elimination phase (figure 2B). Notably, the third patient had the slowest elimination rate, with a minimal concentration decay in the 3-hour post-dose period, this is probably associated with her advanced age (81 years old).

Obesity is another factor associated with prolonged lidocaine T½ β11 and this is confirmed in our patients. In particular, the first patient enrolled, who was both elderly and obese, had the most significant increase in half-life. Several mechanisms may justify this finding, among them an increased absolute volume of distribution, the dose and rate of injection, low plasma protein levels, and diminished hepatic blood-flow and renal function.

Our results also suggest that older patients had a slower distribution phase (figure 2A). Although analogous findings cannot be found in the literature, it has been reported that the volume of distribution of lidocaine is nearly doubled in the elderly,12 confirming that lidocaine distribution can be altered by aging.

Lidocaine exerts its systemic analgesic effect binding multiple molecular targets. However, the greater sensitivity of muscarinic cholinergic and N-methyl-D-aspartate receptors suggests that these receptors are major contributors of lidocaine analgesic effect.13 Previous studies showed that intravenous lidocaine has an analgesic effect when a concentration of 1–4.2 µg/mL is reached14 15 and Koppert et al 15 clearly showed that during lidocaine continuous infusion a clinically relevant analgesia endures beyond its infusion period and continues after its interruption.

Although our study shows that such plasmatic concentration is reached only during the first hour, lidocaine may provide analgesia to the patient beyond this time.

Several mechanisms of action have been hypothesized to provide analgesia after an ESP block such as spread to dorsal and ventral rami, involvement of paravertebral and epidural space and the diffusion along the erector spinae muscles planes, however, the exact mechanism is still a matter of debate.

Considering the above, we propose the systemic analgesic effect of LAs as a further piece of the puzzle to explain the analgesic effect of the ESP block, acknowledging that further studies are necessary to ascertain the extent of its contribution.

Our study has some limitations that need to be discussed.

First, we are reporting a case series of 10 patients. We recognize that this only represents an approximation of lidocaine pharmacokinetic and that further prospective and controlled trials are deemed necessary to be conclusive about this topic.

Second, time to complete the administration of LA was 50 s (IQR 7.5 s), for this reason, Cmax and Tpeak could be influenced by a decrease in the time of administration of the drug. However, lidocaine was administered as fast as possible and for this reason we believe that this bias does not affect the clinical significance of our report.

Third, blood samples were collected at scheduled times. A larger number of samples may have produced a more accurate pharmacokinetic curve.

Fourth, the study used to estimate the bioavailability was based on TBW and not IBW, we recognize this as a possible bias.

Fifth, we use the Broca’s formula for IBW estimation. We recognize that other more precise formulas for IBW calculations exists.

Conclusions

Lidocaine pharmacokinetic after ESP block is well-described by a two compartment model with a rapid and extensive rate of absorption. Nevertheless, its peak concentrations never exceeded the accepted toxicity limit (5 µg/mL). Elimination half-life was slightly prolonged, probably due to the advanced age of some patients.

References

Footnotes

  • Contributors ADC, CB and RP designed the study. All authors participated in the study, wrote and edited the manuscript and approved the final draft.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study protocol and results of this brief report were reviewed and approved by the Institutional Review Board of Padova (Protocol Ref: 2020/22029). The protocol was in accordance with the 1964 Declaration of Helsinki and its later amendments. Informed written consent was obtained from each participant included in the case series.

  • Provenance and peer review Not commissioned; externally peer reviewed.